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1.  Factors Related to Increasing Prevalence of Resistance to Ciprofloxacin and Other Antimicrobial Drugs in Neisseria gonorrhoeae, United States 
Emerging Infectious Diseases  2012;18(8):1290-1297.
What would you do if you had a sexually transmitted disease that was untreatable with antibiotics? That is the situation we may be heading toward. In the United States, gonorrhea is the second most common reportable infection. Over the years, the organism that causes it, N. gonorrhoeae, has acquired resistance to several classes of antibiotics including, most recently, the fluoroquinolones. In fact, widespread resistance led CDC to stop recommending fluoroquinolones for gonorrhea treatment in 2007. Today, cephalosporin-based combination therapy is the last remaining option currently recommended for gonorrhea treatment. Understanding of the causes of drug resistance is needed so that control measures can be improved and the effectiveness of the few remaining drugs can be maintained. This article investigates possible causes for the emergence of fluoroquinolone-resistant N. gonorrhoeae that occurred several years ago. Fluoroquinolone-resistant strains spread in the United States in the late 1990s and spread more rapidly among men who have sex with men (MSM) than among heterosexual men. One possible explanation for the rise in drug resistance, especially among heterosexuals, is acquisition of resistant gonorrhea through travel. Certain drug-resistant strains of N. gonorrhoeae, particularly the multidrug resistant strains (also resistant to penicillin and tetracycline) circulating among MSM, seemed to be able to reach high prevalence levels through domestic transmission, rather than through frequent importation. After resistance emerged in a geographic area, resistant strains appeared among MSM and heterosexuals within several months. When resistance is detected in either MSM or heterosexuals, prevention efforts should be directed toward both populations.
Using data from the Gonococcal Isolate Surveillance Project, we studied changes in ciprofloxacin resistance in Neisseria gonorrhoeae isolates in the United States during 2002–2007. Compared with prevalence in heterosexual men, prevalence of ciprofloxacin-resistant N. gonorrhoeae infections showed a more pronounced increase in men who have sex with men (MSM), particularly through an increase in prevalence of strains also resistant to tetracycline and penicillin. Moreover, that multidrug resistance profile among MSM was negatively associated with recent travel. Across the surveillance project sites, first appearance of ciprofloxacin resistance in heterosexual men was positively correlated with such resistance for MSM. The increase in prevalence of ciprofloxacin resistance may have been facilitated by use of fluoroquinolones for treating gonorrhea and other conditions. The prominence of multidrug resistance suggests that using other classes of antimicrobial drugs for purposes other than treating gonorrhea helped increase the prevalence of ciprofloxacin-resistant strains that are also resistant to those drugs.
PMCID: PMC3414012  PMID: 22840274
Neisseria gonorrhoeae; antimicrobial resistance; men who have sex with men; multidrug resistance; MSM; bacteria; gonorrhea; United States; ciproflaxin; luoroquinolones
2.  Analysis of Neisseria gonorrhoeae Azithromycin Susceptibility in the United States by the Gonococcal Isolate Surveillance Project, 2005 to 2013 
Azithromycin, administered with ceftriaxone, is recommended by the CDC for the treatment of gonorrhea. Many experts have expressed concern about the ease with which Neisseria gonorrhoeae can acquire macrolide resistance. We sought to describe gonococcal azithromycin susceptibility in the United States and to determine whether azithromycin susceptibility has changed over time. We analyzed data from 2005 to 2013 from the Gonococcal Isolate Surveillance Project, a CDC-supported sentinel surveillance network that monitors gonococcal antimicrobial susceptibility. A total of 44,144 N. gonorrhoeae isolates were tested for azithromycin susceptibility by agar dilution methods. The overall azithromycin MIC50 was 0.25 μg/ml, and the MIC90 was 0.5 μg/ml. There were no overall temporal trends in geometric means. Isolates from men who had sex with men had significantly higher geometric mean MICs than isolates from men who had sex exclusively with women. The overall prevalence of reduced azithromycin susceptibility (MIC, ≥2 μg/ml) was 0.4% and varied by year from 0.3% (2006 and 2009) to 0.6% (2013). We did not find a clear temporal trend in gonococcal azithromycin MICs in the United States, and the prevalence of reduced azithromycin susceptibility remains low. These findings support the continued use of azithromycin in a combination therapy regimen for gonorrhea.
PMCID: PMC4335827  PMID: 25451056
3.  Editorial: Cardiac electronic remodeling and susceptibility to arrhythmias: an introduction and brief historical overview 
PMCID: PMC4491600  PMID: 26217235
arrhythmias; cardiac; ventricular fibrillation; atrial fibrillation; gap junctions; electrotronic coupling; myocardial electrical properties; myocardial infarction
4.  Addressing the Achilles' Heel in the HIV Care Continuum for the Success of a Test-and-Treat Strategy to Achieve an AIDS-Free Generation 
Mathematical models and recent data from ecological, observational, and experimental studies show that antiretroviral therapy (ART) is effective for both treatment and prevention of HIV, validating the treatment as prevention (TasP) approach. Data from a variety of settings, including resource-rich and -limited sites, show that patient attrition occurs at each stage of the human immunodeficiency virus (HIV) treatment cascade, starting with the percent unaware of their HIV infection in a population and linkage to care after diagnosis, assessment of ART readiness, receipt of ART, and finally long-term virologic suppression. Therefore, in order to implement TasP, we must first define practical and effective linkage to care, acceptability of treatment, and adherence and retention monitoring strategies, as well as the cost-effectiveness of such strategies. Ending this pandemic will require the combination of political will, resources, and novel effective interventions that are not only feasible and cost effective but also likely to be used in combination across successive steps on the HIV treatment cascade.
PMCID: PMC4141496  PMID: 24926028
HIV; ART; treatment as prevention; test-and-treat; treatment cascade
5.  Evaluation of an Online Program To Teach Microbiology to Internal Medicine Residents 
Journal of Clinical Microbiology  2014;53(1):278-281.
Microbiology rounds are an integral part of infectious disease consultation service. During microbiology rounds, we highlight microbiology principles using vignettes. We created case-based, interactive, microbiology online modules similar to the vignettes presented during microbiology rounds. Since internal medicine residents rotating on our infectious disease elective have limited time to participate in rounds and learn microbiology, our objective was to evaluate the use of the microbiology online modules by internal medicine residents. We asked residents to complete 10 of 25 online modules during their infectious disease elective. We evaluated which modules they chose and the change in their knowledge level. Forty-six internal medicine residents completed assessments given before and after accessing the modules with an average of 11/20 (range, 6 to 19) and 16/20 (range, 9 to 20) correct questions, respectively (average improvement, 5 questions; P = 0.0001). The modules accessed by more than 30 residents included those related to Clostridium difficile, anaerobes, Candida spp., Streptococcus pneumoniae, influenza, Mycobacterium tuberculosis, and Neisseria meningitidis. We demonstrated improved microbiology knowledge after completion of the online modules. This improvement may not be solely attributed to completing the online modules, as fellows and faculty may have provided additional microbiology education during the rotation.
PMCID: PMC4290935  PMID: 25392364
6.  Infectious Disease Physician Assessment of Hospital Preparedness for Ebola Virus Disease 
Open Forum Infectious Diseases  2015;2(3):ofv087.
Background. The first case of Ebola diagnosed in the United States and subsequent cases among 2 healthcare workers caring for that patient highlighted the importance of hospital preparedness in caring for Ebola patients.
Methods. From October 21, 2014 to November 11, 2014, infectious disease physicians who are part of the Emerging Infections Network (EIN) were surveyed about current Ebola preparedness at their institutions.
Results. Of 1566 EIN physician members, 869 (55.5%) responded to this survey. Almost all institutions represented in this survey showed a substantial degree of preparation for the management of patients with suspected and confirmed Ebola virus disease. Despite concerns regarding shortages of personal protective equipment, approximately two thirds of all respondents reported that their facilities had sufficient and ready availability of hoods, full body coveralls, and fluid-resistant or impermeable aprons. The majority of respondents indicated preference for transfer of Ebola patients to specialized treatment centers rather than caring for them locally. In general, we found that larger hospitals and teaching hospitals reported higher levels of preparedness.
Conclusions. Prior to the Centers for Disease Control and Prevention's plan for a tiered approach that identified specific roles for frontline, assessment, and designated treatment facilities, our query of infectious disease physicians suggested that healthcare facilities across the United States were making preparations for screening, diagnosis, and treatment of Ebola patients. Nevertheless, respondents from some hospitals indicated that they were relatively unprepared.
PMCID: PMC4499670  PMID: 26180836
Ebola; healthcare facilities; preparedness
7.  Mortality and Causes of Death Among HIV-Infected Individuals in the Country of Georgia: 1989–2012 
Since 2004, the country of Georgia has provided antiretroviral therapy (ART) to all patients in need. A nationwide retrospective cohort study was conducted to assess the effect of universal access to ART on patterns of mortality and causes of death among HIV-infected individuals in Georgia. All known HIV-infected adult individuals (age ≥18 years) diagnosed from 1989 through 2012 were included. Rates and causes of death were determined using routinely collected data from the national HIV/AIDS database. Causes of death were classified according to the Coding of Death in HIV (CoDe) protocol. Between 1989 and 2012, 3,554 HIV-infected adults were registered in Georgia contributing to 13,572 person-years (PY) of follow-up. A total of 779 deaths were registered during follow-up. The mortality rate peaked in 2004 with 10.74 deaths per 100 PY (95% CI: 7.92–14.24) and significantly decreased after the universal availability of ART to 4.02 per 100 PY (95% CI: 3.28–4.87) in 2012. In multivariate analysis the strongest predictor of mortality was having AIDS at the time of HIV diagnosis (hazard ratio: 5.69, 95% CI: 4.72–6.85). AIDS-related diseases accounted for the majority of deaths (n=426, 54.7%). Tuberculosis (TB) was the leading cause of death accounting for 21% of the total deaths reported. Universal access to ART significantly reduced mortality among HIV-infected patients in Georgia. However, overall mortality rates remain high primarily due to late diagnosis, and TB remains a significant cause of death. Improving rates of early HIV diagnosis and ART initiation may further decrease mortality as well as prevent new HIV and TB infections.
PMCID: PMC4046195  PMID: 24472093
8.  Perspectives of Middle-Aged African American Women in the Deep South on Antiretroviral Therapy Adherence 
AIDS care  2013;26(5):532-537.
Despite evidence of stabilization in some areas of the US, HIV infection in Black women is not declining in the Deep South. Using a phenomenological approach to qualitative inquiry, we investigated women's experiences influencing their adherence to HAART in an urban setting. Inclusion criteria specified Black women who had been aware of their HIV status for at least two years and were engaged in HIV outpatient care. Twelve single face-to-face confidential in-depth semi-structured interviews were conducted from a sample of pre-dominantly middle-aged women retained in care at an HIV clinic in Atlanta, Georgia. Data was analyzed by two independent reviewers and three themes emerged from the group of women's accounts of their experiences. First, sentinel events led to changes in perspective and motivated women to adhere to HAART. Second, recognition that one had the personal strength necessary to cope with HIV fostered adherence. Finally, relationships with healthcare providers especially trust issues surrounding this relationship, impacted adherence both positively and negatively. These findings suggest that HAART adherence is a complex issue among middle-aged urban Black women with HIV in the Deep South. Providers caring for this patient population should recognize that sentinel events, personal strength, and positive healthcare relationships are opportunities to improve adherence.
PMCID: PMC3945157  PMID: 24099510
HIV; HAART; adherence; Black women; South
9.  Racial differences in the validity of self-reported drug use among men who have sex with men in Atlanta, GA 
Drug and alcohol dependence  2014;138:146-153.
Men who have sex with men (MSM), particularly young black MSM, are disproportionately affected in the United States’ HIV epidemic. Drug use may contribute to these disparities, yet previous studies have failed to provide evidence of elevated use among black MSM, relying exclusively on self-reported usage. This study uses biological assays to validate self-reports of drug use and explore the potential for misclassification to distort findings on racial patterns of use in this population.
From an Atlanta-based cohort study of 454 black and 349 white MSM from 2010 to 2012, participants’ self-reported drug use was compared to urine drug screening findings. The sensitivity of self-report was calculated as the proportion reporting recent usage among those who screened positive. Multivariable regression models were constructed to examine racial patterns in self-report, urine-detection, and self-report sensitivity of marijuana and cocaine usage, adjusted for socio-demographic factors.
In analyses that adjusted for age, education, income, sexual orientation, and history of arrest, black MSM were less likely to report recent use of marijuana (P<0.001) and cocaine (P=0.02), but equally likely to screen positive for either drug. This discrepancy between self-reported and urine-detected drug use was explained by significantly lower sensitivity of self-report for black participants (P<0.001 for marijuana, P<0.05 for cocaine).
The contribution of individual drug-related risk behaviors to the HIV disparities between black and white MSM should be revisited with methods that validate self-reports of illegal drug use.
PMCID: PMC4104302  PMID: 24629628
drug use; HIV/AIDS; MSM; race; validity
10.  Isotopic Incorporation Rates and Discrimination Factors in Mantis Shrimp Crustaceans 
PLoS ONE  2015;10(4):e0122334.
Stable isotope analysis has provided insights into the trophic ecology of a wide diversity of animals. Knowledge about isotopic incorporation rates and isotopic discrimination between the consumer and its diet for different tissue types is essential for interpreting stable isotope data, but these parameters remain understudied in many animal taxa and particularly in aquatic invertebrates. We performed a 292-day diet shift experiment on 92 individuals of the predatory mantis shrimp, Neogonodactylus bredini, to quantify carbon and nitrogen incorporation rates and isotope discrimination factors in muscle and hemolymph tissues. Average isotopic discrimination factors between mantis shrimp muscle and the new diet were 3.0 ± 0.6 ‰ and 0.9 ± 0.3 ‰ for carbon and nitrogen, respectively, which is contrary to what is seen in many other animals (e.g. C and N discrimination is generally 0–1 ‰ and 3–4 ‰, respectively). Surprisingly, the average residence time of nitrogen in hemolymph (28.9 ± 8.3 days) was over 8 times longer than that of carbon (3.4 ± 1.4 days). In muscle, the average residence times of carbon and nitrogen were of the same magnitude (89.3 ± 44.4 and 72.8 ± 18.8 days, respectively). We compared the mantis shrimps’ incorporation rates, along with rates from four other invertebrate taxa from the literature, to those predicted by an allometric equation relating carbon incorporation rate to body mass that was developed for teleost fishes and sharks. The rate of carbon incorporation into muscle was consistent with rates predicted by this equation. Our findings provide new insight into isotopic discrimination factors and incorporation rates in invertebrates with the former showing a different trend than what is commonly observed in other animals.
PMCID: PMC4383329  PMID: 25835953
11.  How Well Does the World Health Organization Definition of Domestic Violence Work for India? 
PLoS ONE  2015;10(3):e0120909.
Domestic violence (DV) is reported by 40% of married women in India and associated with substantial morbidity. An operational research definition is therefore needed to enhance understanding of DV epidemiology in India and inform DV interventions and measures. To arrive at a culturally-tailored definition, we aimed to better understand how definitions provided by the World Health Organization and the 2005 India Protection of Women from Domestic Violence Act match the perceptions of behaviors constituting DV among the Indian community. Between September 2012 and January 2013, 16 key informant interviews with experts in DV and family counseling and 2 gender-concordant focus groups of lay community members were conducted in Pune, India to understand community perceptions of the definition of DV, perpetrators of DV, and examples of DV encountered by married women in Pune, India. Several key themes emerged regarding behaviors and acts constituting DV including 1) the exertion of control over a woman’s reproductive decision-making, mobility, socializing with family and friends, finances, and access to food and nutrition, 2) the widespread acceptance of sexual abuse and the influences of affluence on sexual DV manifestations, 3) the shaping of physical abuse experiences by readily-available tools and the presence of witnesses, 4) psychological abuse for infertility, dowry, and girl-children, and 5) the perpetration of DV by the husband and other members of his family. Findings support the need for a culturally-tailored operational definition that expands on the WHO surveillance definition to inform the development of more effective DV intervention strategies and measures.
PMCID: PMC4374684  PMID: 25811374
12.  An application of propensity score weighting to quantify the causal effect of rectal sexually transmitted infections on incident HIV among men who have sex with men 
Exploring causal associations in HIV research requires careful consideration of numerous epidemiologic limitations. First, a primary cause of HIV, unprotected anal intercourse (UAI), is time-varying and, if it is also associated with an exposure of interest, may be on a confounding path. Second, HIV is a rare outcome, even in high-risk populations. Finally, for most causal, non-preventive exposures, a randomized trial is impossible. In order to address these limitations and provide a practical illustration of efficient statistical control via propensity-score weighting, we examine the causal association between rectal STI and HIV acquisition in the InvolveMENt study, a cohort of Atlanta-area men who have sex with men (MSM). We hypothesized that, after controlling for potentially confounding behavioral and demographic factors, the significant STI-HIV association would attenuate, but yield an estimate of the causal effect.
The exposure of interest was incident rectal gonorrhea or chlamydia infection; the outcome was incident HIV infection. To adjust for behavioral confounding, while accounting for limited HIV infections, we used an inverse probability of treatment weighted (IPTW) Cox proportional hazards (PH) model for incident HIV. Weights were derived from propensity score modeling of the probability of incident rectal STI as a function of potential confounders, including UAI in the interval of rectal STI acquisition/censoring.
Of 556 HIV-negative MSM at baseline, 552 (99%) men were included in this analysis. 79 men were diagnosed with an incident rectal STI and 26 with HIV. 6 HIV-infected men were previously diagnosed with a rectal STI. In unadjusted analysis, incident rectal STI was significantly associated with subsequent incident HIV (HR (95%CI): 3.6 (1.4-9.2)). In the final weighted and adjusted model, the association was attenuated and more precise (HR (95% CI): 2.7 (1.2-6.4)).
We found that, controlling for time-varying risk behaviors and time-invariant demographic factors, diagnosis with HIV was significantly associated with prior diagnosis of rectal CT or GC. Our analysis lends support to the causal effect of incident rectal STI on HIV diagnosis and provides a framework for similar analyses of HIV incidence.
Electronic supplementary material
The online version of this article (doi:10.1186/s12874-015-0017-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4369368  PMID: 25888416
STI; HIV; Propensity scores; Survival analysis; Men who have sex with men; Marginal structural models
13.  Population structure of Neisseria gonorrhoeae based on whole genome data and its relationship with antibiotic resistance 
PeerJ  2015;3:e806.
Neisseria gonorrhoeae is the causative agent of gonorrhea, a sexually transmitted infection (STI) of major importance. As a result of antibiotic resistance, there are now limited options for treating patients. We collected draft genome sequence data and associated metadata data on 76 N. gonorrhoeae strains from around the globe and searched for known determinants of antibiotics resistance within the strains. The population structure and evolutionary forces within the pathogen population were analyzed. Our results indicated a cosmopolitan gonoccocal population mainly made up of five subgroups. The estimated ratio of recombination to mutation (r/m = 2.2) from our data set indicates an appreciable level of recombination occurring in the population. Strains with resistance phenotypes to more recent antibiotics (azithromycin and cefixime) were mostly found in two of the five population subgroups.
PMCID: PMC4358642  PMID: 25780762
Antimicrobial resistance; Population structure; Recombination; Whole genome sequence analysis; Genetic admixture
15.  Spirituality, social capital and service: Factors promoting resilience among Expert Patients living with HIV in Ethiopia 
Global public health  2014;9(3):286-298.
People living with HIV (PLHIV) in Ethiopia and other developing nations face numerous challenges to their health and well-being, including poverty, limited healthcare infrastructure, and high levels of societal stigma. Despite these challenges, resilient trajectories have been observed even within such resource-limited settings. In Ethiopia, such resilience is exemplified by the ‘Expert Patients’, HIV-positive lay health workers who function as adherence counsellors, health educators, outreach workers and community advocates. We conducted a multi-method qualitative study with 20 Expert Patients in Addis Ababa, Ethiopia in order to understand pathways to resilience in this select population. Participants described 3 key mechanisms of resilient coping: (1) The use of spirituality and faith-based practices to manage psychological difficulties associated with living with HIV; (2) Utilisation of social capital from family and community networks as a buffer against the psychological and economic consequences of societal stigma; and (3) Serving others as a mechanism for finding optimism and purpose in life. Interventions designed to facilitate and/or augment these social processes in the wider community may be promising strategies for improving health among PLHIV in Ethiopia and other resource-limited settings.
PMCID: PMC4033693  PMID: 24520996
Ethiopia; peer educators; HIV/AIDS; resilience; social capital
16.  Failure to Identify HIV-Infected Individuals in a Clinical Trial Using a Single HIV Rapid Test for Screening 
HIV clinical trials  2014;15(2):62-68.
In the HIV Prevention Trials Network (HPTN) 061 study, 8 (2.3%) of 348 HIV-infected participants identified as HIV uninfected at study enrollment using a single HIV rapid test for screening were found to be HIV infected after additional testing.
To evaluate the performance of different HIV assays for detection of HIV infection in HPTN 061 participants with missed infection and individuals with viral suppression.
Plasma samples from 8 HPTN 061 participants, 17 elite controllers, and 101 individuals on antiretroviral treatment (ART) were tested for HIV with 3 rapid tests, 2 laboratory-based immunoassays, and a Western blot assay. The HPTN 061 samples were also tested with 2 HIV RNA assays and an antiretroviral drug assay.
Of the 8 HPTN 061 participants with missed infection, 1 was an elite controller, 1 was taking ART, 2 were missed because of testing or clerical errors, 1 had recent HIV infection (identified using a multi-assay algorithm), and 3 had acute HIV infection. Two (1.7%) of 118 individuals with viral suppression (both taking ART) had at least 1 false-negative test.
In clinical trials, HIV infections can be missed for a variety of reasons. Using more than one assay to screen for HIV infection may reduce the number of missed infections.
PMCID: PMC4167641  PMID: 24710920
antiretroviral therapy; elite controller; HIV; rapid test; viral suppression
17.  Outcomes by Sex Following Treatment Initiation With Atazanavir Plus Ritonavir or Efavirenz With Abacavir/Lamivudine or Tenofovir/Emtricitabine 
Smith, Kimberly Y. | Tierney, Camlin | Mollan, Katie | Venuto, Charles S. | Budhathoki, Chakra | Ma, Qing | Morse, Gene D. | Sax, Paul | Katzenstein, David | Godfrey, Catherine | Fischl, Margaret | Daar, Eric S. | Collier, Ann C. | Bolivar, Hector H. | Navarro, Sandra | Koletar, Susan L. | Gochnour, Diane | Seefried, Edward | Hoffman, Julie | Feinberg, Judith | Saemann, Michelle | Patterson, Kristine | Pittard, Donna | Currin, David | Upton, Kerry | Saag, Michael | Ray, Graham | Johnson, Steven | Santos, Bartolo | Funk, Connie A. | Morgan, Michael | Jackson, Brenda | Tebas, Pablo | Thomas, Aleshia | Kim, Ge-Youl | Klebert, Michael K. | Santana, Jorge L. | Marrero, Santiago | Norris, Jane | Valle, Sandra | Cox, Gary Matthew | Silberman, Martha | Shaik, Sadia | Lopez, Ruben | Vasquez, Margie | Daskalakis, Demetre | Megill, Christina | Shore, Jessica | Taiwo, Babafemi | Goldman, Mitchell | Boston, Molly | Lennox, Jeffrey | del Rio, Carlos | Lane, Timothy W. | Epperson, Kim | Luetkemeyer, Annie | Payne, Mary | Gripshover, Barbara | Antosh, Dawn | Reid, Jane | Adams, Mary | Storey, Sheryl S. | Dunaway, Shelia B. | Gallant, Joel | Wiggins, Ilene | Smith, Kimberly Y. | Swiatek, Joan A. | Timpone, Joseph | Kumar, Princy | Moe, Ardis | Palmer, Maria | Gothing, Jon | Delaney, Joanne | Whitely, Kim | Anderson, Ann Marie | Hammer, Scott M. | Yin, Michael T. | Jain, Mamta | Petersen, Tianna | Corales, Roberto | Hurley, Christine | Henry, Keith | Bordenave, Bette | Youmans, Amanda | Albrecht, Mary | Pollard, Richard B. | Olusanya, Abimbola | Skolnik, Paul R. | Adams, Betsy | Tashima, Karen T. | Patterson, Helen | Ukwu, Michelle | Rogers, Lauren | Balfour, Henry H. | Fox, Kathy A. | Swindells, Susan | Van Meter, Frances | Robbins, Gregory | Burgett-Yandow, Nicole | Davis, Charles E. | Boyce, Colleen | O'Brien, William A. | Casey, Gerianne | Morse, Gene D. | Hsaio, Chiu-Bin | Meier, Jeffrey L. | Stapleton, Jack T. | Mildvan, Donna | Revuelta, Manuel | Currin, David | El Sadr, Wafaa | Loquere, Avelino | El-Daher, Nyef | Johnson, Tina | Gross, Robert | Maffei, Kathyrn | Hughes, Valery | Sturge, Glenn | McMahon, Deborah | Rutecki, Barbara | Wulfsohn, Michael | Cheng, Andrew | Dix, Lynn | Liao, Qiming
This clinical trial identifies a significantly earlier time to virologic failure in women randomized to atazanavir/ritonavir compared to women randomized to efavirenz.
Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex.
Methods. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1–infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII).
Results. Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex.
Conclusions. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential.
Clinical Trials Registration NCT00118898.
PMCID: PMC3905755  PMID: 24253247
sex; atazanavir; efavirenz; abacavir; tenofovir
18.  Myocardial electrotonic response to submaximal exercise in dogs with healed myocardial infarctions: evidence for β-adrenoceptor mediated enhanced coupling during exercise testing 
Introduction: Autonomic neural activation during cardiac stress testing is an established risk-stratification tool in post-myocardial infarction (MI) patients. However, autonomic activation can also modulate myocardial electrotonic coupling, a known factor to contribute to the genesis of arrhythmias. The present study tested the hypothesis that exercise-induced autonomic neural activation modulates electrotonic coupling (as measured by myocardial electrical impedance, MEI) in post-MI animals shown to be susceptible or resistant to ventricular fibrillation (VF).
Methods: Dogs (n = 25) with healed MI instrumented for MEI measurements were trained to run on a treadmill and classified based on their susceptibility to VF (12 susceptible, 9 resistant). MEI and ECGs were recorded during 6-stage exercise tests (18 min/test; peak: 6.4 km/h @ 16%) performed under control conditions, and following complete β-adrenoceptor (β-AR) blockade (propranolol); MEI was also measured at rest during escalating β-AR stimulation (isoproterenol) or overdrive-pacing.
Results: Exercise progressively increased heart rate (HR) and reduced heart rate variability (HRV). In parallel, MEI decreased gradually (enhanced electrotonic coupling) with exercise; at peak exercise, MEI was reduced by 5.3 ± 0.4% (or -23 ± 1.8Ω, P < 0.001). Notably, exercise-mediated electrotonic changes were linearly predicted by the degree of autonomic activation, as indicated by changes in either HR or in HRV (P < 0.001). Indeed, β-AR blockade attenuated the MEI response to exercise while direct β-AR stimulation (at rest) triggered MEI decreases comparable to those observed during exercise; ventricular pacing had no significant effects on MEI. Finally, animals prone to VF had a significantly larger MEI response to exercise.
Conclusions: These data suggest that β-AR activation during exercise can acutely enhance electrotonic coupling in the myocardium, particularly in dogs susceptible to ischemia-induced VF.
PMCID: PMC4318283  PMID: 25698976
electrotonic coupling; β-adrenoceptor stimulation; exercise; arrhythmic risk; myocardial infarction
19.  Case Management: Steadfast Resource for Addressing Linkage to Care and Prevention with Hospitalized HIV-Infected Crack Users 
Interviews were conducted among HIV-positive inpatients in Miami, Florida and Atlanta, Georgia to examine whether having a case manager was associated with improved outcomes. We explored whether current use of a case manager was associated with unprotected sex, HIV care, use of antiretroviral medications, and referral to case management at time of diagnosis. Outcomes among patients who received case management were compared to those without a case manager. Participants with a current case manager were significantly more likely to take HIV medications, have obtained HIV care within the past six months, and have been referred to case management when first diagnosed. They were also significantly less likely to engage in unprotected sex within the last six months. Interventions that link HIV positive patients with a case manager may improve HIV health-seeking behaviors and reduce sexual risk engagement which may lead to improved clinical results.
PMCID: PMC4307800  PMID: 25635176
HIV Case Management; Drug use among PLWH; HIV Care; ART Adherence
20.  Nondisclosure of HIV Status in a Clinical Trial Setting: Antiretroviral Drug Screening Can Help Distinguish Between Newly Diagnosed and Previously Diagnosed HIV Infection 
In The HIV Prevention Trials Network 061 study, 155 human immunodeficiency virus (HIV)–infected men reported no prior HIV diagnosis; 83 of those men had HIV RNA levels of <1000 copies/mL at enrollment. Antiretroviral drug testing revealed that 65 of the 83 (78.3%) men were on antiretroviral treatment. Antiretroviral drug testing can help distinguish between newly diagnosed and previously diagnosed HIV infection.
PMCID: PMC3864502  PMID: 24092804
HIV; antiretroviral; self-report; MSM; new diagnosis
21.  Reduction of early reperfusion injury with the mitochondria-targeting peptide Bendavia 
We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and no-reflow across several experimental models. The purpose of this study was to determine the therapeutic timing and mechanism of action that underlie Bendavia’s cytoprotective property. In rabbits exposed to in vivo ischemia/reperfusion (30/180 min), Bendavia administered 20 min prior to reperfusion (0.05mg/kg/hr, i.v.) reduced myocardial infarct size by ~50% when administered for either 1 or 3 hours of reperfusion. However, when Bendavia perfusion began just 10 min after the onset of reperfusion, the protection against infarction and no–reflow was completely lost, indicating that the mechanism of protection is occurring early in reperfusion. Experiments in isolated mouse liver mitochondria found no discernible effect of Bendavia on blocking the permeability transition pore, and studies in isolated heart mitochondria showed no effect of Bendavia on respiratory rates. As Bendavia significantly lowered reactive oxygen species (ROS) levels in isolated heart mitochondria, the ROS-scavenging capacity of Bendavia was compared to well-known ROS scavengers using in vitro (cell-free) systems that enzymatically generate ROS. Across doses ranging from 1nM to 1mM, Bendavia showed no discernible ROS-scavenging properties, clearly differentiating itself from prototypical scavengers. In conclusion, Bendavia is a promising candidate to reduce cardiac injury when present at onset of reperfusion, but not after reperfusion has already commenced. Given that both infarction and no-reflow are related to increased cellular ROS, Bendavia’s protective mechanism of action likely involves reduced ROS generation (as opposed to augmented scavenging) by endothelial and myocyte mitochondria.
PMCID: PMC4103197  PMID: 24288396
mitochondria; reactive oxygen species; reperfusion; heart; peptide
We examined parameters of sexual partnerships, including respondents’ participation in concurrency, belief that their partner had concurrent partnerships (partners’ concurrency), and partnership intervals, among the 2,099 women in HIV Prevention Trials Network 064, a study of women at high risk for HIV infection, in ten US communities.
We analyzed baseline survey responses about partnership dates to determine prevalence of participants’ and partners’ concurrency, intervals between partnerships, knowledge of whether recent partner(s) had undergone HIV testing, and intercourse frequency during the preceding 6 months.
Prevalence of participants’ and partners’ concurrency was 40% and 36% respectively; 24% of respondents had both concurrent partnerships and non-monogamous partners. Among women with >1 partner and no concurrent partnerships themselves, the median gap between partners was one month. Multiple episodes of unprotected vaginal intercourse with >2 of their most recent partners was reported by 60% of women who had both concurrent partnerships and non-monogamous partners, 50% with only concurrent partners and no partners’ concurrency, and 33% with only partners’ concurrency versus 14% of women with neither type of concurrency (p<.0001). Women who had any involvement with concurrency were also more likely than women with no concurrency involvement to report lack of awareness of whether recent partners had undergone HIV testing (participants’ concurrency 41%, partners’ concurrency 40%, both participants’ and partners’ concurrency 48%, neither 17%; p<.0001).
These network patterns and short gaps between partnerships may create substantial opportunities for HIV transmission in this sample of women at high risk for HIV infection.
PMCID: PMC4172374  PMID: 24056163
23.  Early Warning Indicators for First-Line Virologic Failure Independent of Adherence Measures in a South African Urban Clinic 
AIDS Patient Care and STDs  2013;27(12):657-668.
We sought to develop individual-level Early Warning Indicators (EWI) of virologic failure (VF) for clinicians to use during routine care complementing WHO population-level EWI. A case-control study was conducted at a Durban clinic. Patients after≥5 months of first-line antiretroviral therapy (ART) were defined as cases if they had VF [HIV-1 viral load (VL)>1000 copies/mL] and controls (2:1) if they had VL≤1000 copies/mL. Pharmacy refills and pill counts were used as adherence measures. Participants responded to a questionnaire including validated psychosocial and symptom scales. Data were also collected from the medical record. Multivariable logistic regression models of VF included factors associated with VF (p<0.05) in univariable analyses. We enrolled 158 cases and 300 controls. In the final multivariable model, male gender, not having an active religious faith, practicing unsafe sex, having a family member with HIV, not being pleased with the clinic experience, symptoms of depression, fatigue, or rash, low CD4 counts, family recommending HIV care, and using a TV/radio as ART reminders (compared to mobile phones) were associated with VF independent of adherence measures. In this setting, we identified several key individual-level EWI associated with VF including novel psychosocial factors independent of adherence measures.
PMCID: PMC3868291  PMID: 24320011
24.  Dose-Dependent Hemodynamic, Biochemical, and Tissue Oxygen Effects of OC99 following Severe Oxygen Debt Produced by Hemorrhagic Shock in Dogs 
We determined the dose-dependent effects of OC99, a novel, stabilized hemoglobin-based oxygen-carrier, on hemodynamics, systemic and pulmonary artery pressures, surrogates of tissue oxygen debt (arterial lactate 7.2 ± 0.1 mM/L and arterial base excess −17.9 ± 0.5 mM/L), and tissue oxygen tension (tPO2) in a dog model of controlled severe oxygen-debt from hemorrhagic shock. The dose/rate for OC99 was established from a pilot study conducted in six bled dogs. Subsequently twenty-four dogs were randomly assigned to one of four groups (n = 6 per group) and administered: 0.0, 0.065, 0.325, or 0.65 g/kg of OC99 combined with 10 mL/kg lactated Ringers solution administered in conjunction with 20 mL/kg Hextend IV over 60 minutes. The administration of 0.325 g/kg and 0.65 g/kg OC99 produced plasma hemoglobin concentrations of 0.63 ± 0.01 and 1.11 ± 0.02 g/dL, respectively, improved systemic hemodynamics, enhanced tPO2, and restored lactate and base excess values compared to 0.0 and 0.065 g/kg OC99. The administration of 0.65 g/kg OC99 significantly elevated pulmonary artery pressure. Plasma hemoglobin concentrations of OC99 ranging from 0.3 to 1.1 g/dL, in conjunction with colloid based fluid resuscitation, normalized clinical surrogates of tissue oxygen debt, improved tPO2, and avoided clinically relevant increases in pulmonary artery pressure.
PMCID: PMC4227330  PMID: 25405028

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